FSGS AND Transplant

Sushma Bhusal 11.17.15

Case

48 yo AA female with h/o ESRD from FSGS, s/p DDRT in 2010, presented with dysuria, suprapubic and RLQ pain x 3 days on 11/8/15 Had C diff 3 months prior, treated with 2 courses of Flagyl Also UTI around the same time (multiple)

HPI

DDRT in Feb 2010, course complicated by ureteral reimplantation, AMR, ATN. Cr around eventually stabilized around 1.3 Cr increased to 1.6 in 10/2010, increased proteinuria, tx biopsy with 1/23 glomeruli FSGS Treated with plasmapheresis and high dose Pred, stopped in 2013 Cr stabilized around mid 2s until 3/2015, slow rise to 3s since then

History Contd PMH/PSH – DDRT for ESRD secondary to FSGS – Recurrent FSGS – RIJ DVT – Hyperthyroidism – Recurrent UTIs – C diff

FH: Mother and sister with Ca breast SH: Non smoker, social drinker, no illicits

Meds

Prograf 5 mg bid Prednisone 5 mg po d Sodium bicarbonate 650 mg bid Ferrous sulfate 1 tid Omeprazole 20 mg po d Septra SS q other day Vasotec 5 mg bid

Physical Exam

Vitals: Temp 98.8, HR 89, RR 18, BP 122/70, O2 Sat 99% General appearance: alert, NAD HEENT: sclera anicteric, mmm Lungs: clear to auscultation bilaterally Heart: regular rate and rhythm, S1, S2 normal, no m/r/g Abdomen: soft, RLQ tenderness; bowel sounds normal Extremities: no edema

Labs

CMP CBC

7.6 38.2

12.3

226 19

111

5.4

139

4.4

53 88

Alk Phos: 69 Albumin: 3.1 Total protein: 6.1

Liver test

Total Bilirubin: 0.5 Direct Bilirubin: 0 AST: 11 ALT: 18

Ca+: 9.2 Phos: 5.3

Tacrolimus: 7.4

UA: Small blood Protein Large RBC – 7 WBC – 10 No bacteria LE / Nit - Neg

Renal US

Interval development of hydroureteronephrosis of the right lower quadrant renal allograft, with area transplant and periureteral stranding c/f infection vs. recent obstruction

Hospital Course

Treated with Ceftriaxone, unasyn Urine culture negative Diarrhea resolved, C diff negative Renal biopsy undertaken Cr stabilized 2.4-2.6 No Urology intervention for mild hydro

Differential Diagnosis

Pre-renal AKI in the setting of diarrhea ATN Acute Rejection Chronic progressive disease Recurrent FSGS

Biopsy

Biopsy

KIDNEY, TRANSPLANT: PERCUTANEOUS NEEDLE CORE BIOPSY

- ACUTE TUBULAR INJURY, DIFFUSE AND MODERATE - CHRONIC INTERSTITIAL INFLAMMATORY CELL INFILTRATE, DIFFUSE AND MODERATE - NEGATIVE C4D STAIN IN PERITUBULAR CAPILLARY - NEGATIVE SV40 STAIN FOR POLYOMA VIRUS - INTERSTITIAL FIBROSIS/TUBULAR ATROPHY, 50-60 % - GLOBAL GLOMERULOSCLEROSIS, 14/45

FSGS and Transplant

Introduction Pathophysiology Treatment options

Introduction

Accounts for 20% of NS in children and 40% in adults Global incidence of FSGS estimated at 8 cases/million/yr In US, prevalence 4%, lifetime risk for FSGS estimated at 0.2% for European Americans and 0.7% for AA Progression to ESRD occurs in 40–60% of FSGS pts within 10 - 20 years from diagnosis, making FSGS mc primary glomerular disease in dialysis patients

Fogo, A. B. Nat. Rev. Nephrol. 2015 Cravedi et al. Am J Transplant. 2013 Feb D’agati et al. N Engl J Med 2011

Forms/Types

Currently recognized forms 1. Genetic 2. Adaptive (post-adaptive) 3. Virus associated 4. Drug-induced 5. Primary (idiopathic)

D’agati et al. N Engl J Med 2011 Cravedi et al. Am J Transplant. 2013 Feb

Forms/Types Forms Characteristics

Genetic

• a/w mutations > 20 genes, • encoded in the nuclear or mitochondrial genome • encoding a range of molecules, viz slit diaphragm and actin cytokeleton

Post adaptive • mismatch b/w physiological load (partly body size and other determinants of glomerular BF) and glomerular filtration surface (partly nephron number),

• leads to podocyte stress, podocyte detachment and loss

Virus associated • Parvovirus B19 and HIV • Via direct viral infection of the podocyte, circulating viral proteins or

inflammatory cytokines released by other infected cells that interact with podocyte receptors

Drug induced • act on podocyte (pamidronate, interferon-alpha) • damage the tubulointerstitium (e.g. lithium, cyclosporine, tenofovir

Idiopathic

Pathological variants

NOS

Cellular

Perihilar

Collapse Tip

Pathophysiology of Recurrence

27 yo patient with ESRD caused by primary FSGS, developed severe nephrotic syndrome shortly after receiving a kidney tx from 24 yo sister Graft biopsy D6: FSGS recurrence, podocyte foot-process effacement and loss of the interdigitating arrangements. Severe hypoalbuminemia, rapidly deteriorating graft function + an intra-abdominal hematoma, renal allograft removal on D14 Kidney transplanted to 66 yo with ESRD from DM2 nephropathy Immediately post re-transplantation, the graft regained function, proteinuria decreased, and glomerular lesions regressed, shown by allograft bx on D8 and D25 after re-transplantation

Gallon et al NEJM 2012

Risk factors for Recurrence

Younger age (especially in children <6 at FSGS onset) Nonblack race Rapid progression to ESRD in the native kidney (<3 years) Heavy proteinuria pre-transplantation period Loss of previous allografts to recurrence

Cravedi et al. Am J Transplant. 2013 Feb

Pathophysiology of Recurrence

Insights from Buffalo Rats – Buffalo/Mna rats develop spontaneous proteinuria a/w renal

histology of FSGS

– transplanted kidney from a healthy MHC-compatible LEW.1W, FSGS recurs

– Buffalo/Mna kidneys transplanted into normal LEW.1W rats, proteinuria and renal lesions regress

Cravedi et al. Am J Transplant. 2013 Feb

Insights from Buffalo Rats Role of T cells?

– Studies in these rats: cells in kidney infiltrate were macrophages, monocytes and Th2 cells

– Rx with deoxyspergualin derivative LF15-0195 a/w the formation of Treg, reduction in proteinuria in the initial kidney disease and prevention of recurrence

Inherited podocyte defects: recurrence in NPHS2 gene mutation – ? Inherited defects elicit immune response to accelerate

glomerulosclerosis

Cravedi et al. Am J Transplant. 2013 Feb

Circulating Factors

suPAR

Cardiotrophin-like cytokine 1 (CLC-1) – a member of the interleukin-6 family, – Decreases nephrin expression in cultured podocytes and its blockade

reverses the permeability effect of sera from FSGS patient

Protein tyrosine phosphatase receptor-O (PTPro) – transmembrane protein expressed on the apical surface of podocyte

foot processes – activity is required to maintain glomerular permeability – Mechanism of PTPro phosphatase activity in glomerular filtration

and the identities of the PTPro ligand and substrate unclear

Reiser et al. Advances in CKD 2014

Circulating urokinase receptor as a cause of FSGS Reiser et al. Nature Medicine 2011

uPAR is a (GPI)-anchored three-domain (DI, DII and DIII) protein, identified as a cellular receptor for urokinase, also as a versatile signaling orchestrator through association with other transmembrane receptors, including integrins

uPAR can be released from the plasma membrane as a soluble molecule (suPAR) by cleavage of the GPI anchor

can be further cleaved in the linker region between DI and DII, releasing fragmentS

circulating protein ranging from 20 to 50 kDa

enhanced circulating suPAR deposits into the glomeruli, allowing activation of podocyte β3 integrin, which drives podocyte foot process effacement, proteinuria and initiation of FSGS

suPAR measurement in the serum of subjects with glomerular disease

Pre-transplantation suPAR serum concentration may be a predictor of heightened risk of recurrent FSGS after

transplantation

suPAR serum concentrations and podocyte β3 integrin activity determine Rx response to plasmapheresis in recurrent FSGS

suPAR activates β3 integrin and causes foot process effacement in Plaur−/− mouse kidneys and albuminuria in Plaur−/− mice

Sustained overexpression of suPAR in the blood of wild-type mice leads to an FSGS-like glomerulopathy. (

Reiser et al. Nature Medicine 2011

Administration of blocking antibody to uPAR ameliorates suPAR-caused kidney damage

Reiser et al. Nature Medicine 2011

Pitfalls

Serum levels of suPAR above the suggested threshold of 3000 pg/mL were found in patients without recurrent FSGS Plasma suPAR levels elevated in several inflammatory conditions viz chronic infections (including tuberculosis and malaria), bacterial pneumonia, bacterial and viral CNS infections, sepsis and various cancers Single center cohort of 23 patients – serum suPAR levels were similar amongst idiopathic FSGS secondary FSGS and

MCD – Did not predict responsiveness to steroid therapy in patients with idiopathic

FSGS or MCD

Uninterpretable with low GFR

Progression of FSGS injury

Various insults directed to or inherent within the podocyte nephrotic proteinuria Wharram et al. induced precise levels of podocyte depletion by titrating dose of diphtheria toxin in transgenic mice – Podocyte depletion <20%: transient proteinuria and mesangial

expansion – loss of 20% to 40% of podocytes: persistent proteinuria and focal

glomerulosclerosis, no progressive renal function decline – >40% podocyte loss: progressive glomerular failure

Progression of FSGS injury

Chimeric model: subpopulation of podocytes express toxin receptor, podocyte injury and dedifferentiation shown to spread to neighboring toxin-resistant podocytes Podocytes shed into the urine for months after a brief toxin exposure Local propagation of injury: podocyte loss requires that neighboring podocytes must undergo hypertrophy to cover a larger area of the capillary loop can place stress on the podocyte

Cravedi et al. Am J Transplant. 2013 Feb

Possible pathways for regeneration of podocytes from PEC migration to the glomerular tuft and for the development of

sclerosis

Fogo, A. B. Nat. Rev. Nephrol. 2015

Proposed Mechanism of FSGS Recurrence

Treatment algorithm for FSGS

D’agati et al. N Engl J Med 2011

Treatment of FSGS recurrence

Challenging, with none of the multiple approaches providing consistent efficacy

1. Plasmapheresis 2. Calcineurin inhibitors 3. Rituximab 4. Renin angiotensin system inhibitors 5. CTLA4 Inhibition 6. Galactose and adalimumab

Treatment of FSGS recurrence: Plasmapheresis

Rationale: potential existence of circulating factor Mostly retrospective studies Prospective study: Gohh et al – 10 pts with high risk for recurrence – 8 PP in perioperative period – Recurrence : proteinuria > 3 gm/24 hr/biopsy findings – 3 patients had recurrence

Gohh et al. Am J Transplant. 2005

Treatment of FSGS recurrence: CNI

Rationale: – T cell inhibition (small studies) – antiproteinuric effect by inhibition of calcineurin-mediated

dephosphorylation of synaptopodin, critical for stabilizing the actin cytoskeleton in podocyte

Higher trough levels to overcome hypercholesterolemia Prospective cohort study in children by Salomon et al (n=17), 14 with CR of proteinuria maintained for several years, trough 250-350 ng/ml (IV converted to PO in 3-4 weeks)

CsA studies

Treatment of FSGS recurrence: Rituximab

Rationale: – Depletion of a circulating autoAb or interference with the

presentation of B-cell Ag – rituximab binds directly to SMPDL-3b protein (implicated in

actin remodeling), prevents its down regulation in podocyte

Rituximab Cases in recurrent FSGS

Renin angiotensin system inhibitors

Few cases reported on the use of RAS inhibitors in patients with FSGS recurrence Freiberger et al: Case with FSGS recurrence after transplant that safely achieved proteinuria remission with intensified RAS inhibition via triple RAS therapy: ACE-I, ARB and a renin inhibitor Watch for hyperk, elevated Cr

CTLA4 Inhibition

Mundel et al. NEJM 2013 – described 5 pts with FSGS and proteinuria with B7-1 immunostaining of

podocytes in kidney-biopsy specimens. – Abatacept (CTLA 4 Ig)induced partial or complete remissions of

proteinuria in these patients

Johnson et al. Ped Nephrol 2015 – 1 patient with MCD, 1 patient with primary FSGS and 3 patients with

recurrent FSGS after tx received CD80 blocking Abs (abatacept or belatacept)

– Urinary CD80 and CTLA-4 levels were measured by ELISA. Glomeruli were stained for CD80.

– Results: CD 80 undetectable, resolution of proteinuria in MCD, no response in FSGS patients

– Conclusion: role of podocyte CD80 in dev of protienuria in MCD, not so in FSGS

Thank You